Aminoglycoside antibiotics have a broad antibacterial spectrum against gram-positive and gram-negative bacteria, and it is said that their action mechanism is based on inhibition of bacterial protein synthesis. Since even after blood concentration of the aminoglycoside antibiotics is decreased to a concentration of MIC (minimum inhibitory concentration) or less, and the aminoglycoside antibiotics exhibit post-antibiotic effect (PAE) on the inhibition of bacterial growth, it is known that the aminoglycoside antibiotics show long-lasting inhibitory effect on the inhibition of bacterial growth even after a short period of contact with gram-positive and gram-negative bacteria. For this reason, various aminoglycoside antibiotics such as gentamicin, tobramycin, streptomycin, amikacin, arbekacin, and the like have been widely used via systemic administration of oral preparations, injections, or the like, or via topical administration of eye drops, nose drops, ear drops or the like for the treatment of infectious diseases caused by Pseudomonas, Proteus, Escherichia coli or Staphylococcus such as hematosepsis, bronchitis, pneumonia, pyelitis, cystitis, peritonitis, blepharitis, hordeolum, conjunctivitis, keratitis, dacryocystitis, tympanititis, external otitis, parasinusitis, and the like.
As mentioned above, aminoglycoside antibiotics are effective against infectious diseases. It is, however, important to simultaneously suppress inflammations associated with infection in infectious diseases. It is known that combination use of antibiotics with anti-inflammatory agents can ameliorate quickly infectious site of inflammations. With respect to aqueous solution preparations, a combination drug of an aminoglycoside antibiotic with a steroidal anti-inflammatory agent, for example, a combination drug of fradiomycin sulfate with betamethasone sodium phosphate has been practically used in the form of an aqueous solution preparation in the field of ophthalmology and otorhinolaryngology.
However, there is a problem that said combination drugs cause adverse effects which are known in steroid preparations, such as induction of infection, exacerbation of infectious diseases, secondary hypocorticosteroidism, glaucoma, posterior subcapsular cataract, and the like. For this reason, a combination solution preparation of an aminoglycoside antibiotic with a non-steroidal antiinflammatory agent, having no side effects as mentioned above, is considered to be very useful. However, for example, when tobramycin is combined with diclofenac sodium which is a non-steroidal antiinflammatory agent, there is a problem that precipitation or suspension formation occurs (see Non-patent literature: Ion-paired codrug for increased ocular absorption, Proceed. Int'Symp. Control. Rel. Bioact. Mater., 24 (1997)), making it difficult to prepare an aqueous solution preparation comprising an aminoglycoside antibiotic and a nonsteroidal anti-inflammatory agent.
Bromfenac is a non-steroidal antiinflammatory agent represented by the formula (I):
and its chemical name is 2-amino-3-(4-bromobenzoyl)phenylacetic acid. Bromfenac is effective against inflammatory diseases (e.g. blepharitis, conjunctivis, scleritis, postoperative inflammation) of the extraocular segment or the anterior ocular segment in the field of ophthalmology, and in particular, its efficacy for treating uveitis is equal to nonsteroidal antiinflammatory agents which have previously been used (see Patent literature 1: Japanese patent no. 2683676 corresponding to U.S. Pat. No. 4,910,225). Bromfenac has been practically used as its sodium salt in the form of eye drops in the field of ophthalmology.
However, with respect to a combined aqueous solution preparation comprising bromfenac and an aminoglycoside antibiotic, stable combined preparations have not yet been known, due to the difficulty in formulation of the above aminoglycoside antibiotic with the non-steroidal antiinflammatory agent.